"Trotman and colleagues then turned to human prostate cancer cells, which they treated with a drug that inhibits PHLPP2. This lowered MYC levels and caused the cells to stop proliferating and die.
PHLPP2 does not appear to perform any essential functions in healthy cells, so researchers suggest the enzyme could be an attractive way to indirectly target MYC in metastatic prostate cancer and possibly other cancers, too.
"Our results suggest that targeted efforts to design pharmacologically relevant PHLPP2 inhibitors could result in very efficient new drugs that suppress MYC-driven cancer," Trotman says."
Given their results the team hypothesized that using a drug compound to directly inhibit PHLPP2 might have an anticancer effect by suppressing the MYC protein. Tests with a PHLPP2 inhibitor termed NCI45586 led to dose-dependent reductions in total Myc protein in two GEM mouse-derived cell lines that were known to drive prostate cancer through Myc. Pharmacologic inhibition of phlpp2 also led to increased cell death in another mouse prostate cancer cell line, and in cells derived from the RapidCaP GEM model.
"Treatment using the PHLPP2 inhibitor reduced cell viability and proliferation, and increased cell death in a human metastatic prostate cancer cell line. Similar results were obtained in bone metastasis-derived prostate cancer cells. “Our results with the NCI45586 tool compound closely mirrored those from genetic ablation of the PHLPP2 gene, a proof of concept that could lead to the development of pharmacologically relevant drugs,” the team stated “ … our results showed that the PHLPP2 function of protecting MYC can be targeted to kill PTEN mutant cells.”
Encouragingly, RapidCaP GEM mice in which the Phlpp2 gene was knocked out (i.e., mice lacking Pten, Tp53, and Phlpp2) exhibited significantly lower overall disease burden compared with the original RapidCaP animals after 10 months. The triple knockouts also didn’t develop metastases, whereas the Pten/Tp53 knockouts developed metastases at multiple sites.
Knocking out Phlpp2 didn’t appear to have any adverse effects on normal cells. “Taken together, our in vivo genetic validation data demonstrated that Phlpp2 is required for the tumor and metastasis formation seen in the Pten/Trp53-mutant RapidCaP model,” the investigators commented. “The PHLPP2 phosphatase is an attractive drug target for several reasons. First, we show that Pten-deficient metastatic PC cells fully depend on it. In contrast, normal cells do not, as demonstrated by the normal viability of the phlpp2 knockout mice. Next, general advances in structural understanding of phosphatases have led to a “renaissance” of inhibitor design. By looking beyond the active site, novel allosteric inhibitors can now shut down phosphatases that used to be considered “undruggable.”
The team’s results are particularly promising given that scientists have to date been unable to find a way to target the MYC protein directly. Each year an estimated 450,000 people in the U.S. are diagnosed with a cancer that is driven by MYC. “Thus, our work introduces the PHLPP2 phosphatase as an unexpected, yet druggable, driver of MYC-driven PC and its progression,” the team concluded."
Ty George..for posting this very interesting article. like to hear from others on this .can only hope that there are new drugs or better yet cures coming soon..
Very interesting find George. MYC is another fascinating target historically described as late stage, rare and fuzzy to this PCa patient/advocate/lay-researcher's ears. Tho listening better is in order! Dr. Google sez it's "one of the most frequently mutated, widely studied, and overexpressed genes implicated in cancer." A “master regulator” and "involved broadly in many cancers, in which its expression is estimated to be elevated or deregulated in up to 70% of human cancers." Not just us-guys with PCa. That's all good in developing a drug target/therapy.
PHLPP2 is way inside-baseball (to me!.) A "back door to MYC" and encouraging non-toxicity (so far) in humans. This area could/might catch fire and attract big research and drug development dollars--or not. Our FDA sets very high bars to save us from toxicity risk--sorta like NASA and FAA with human-flight safety requirements--(yes, twinge of irony intended...) T'will be interesting to watch.
Wouldn't it be nice if PCa kept pole position (at least per this press release), or at least nose-to-nose with breast cancer treatment development? The lady-(near)specific diseases (love-'em!) seem to represent a major magnetism and lead (10+ years??) in investment of therapy development dollars. Guys speaking up (and opening our wallets?) might keep us more near head to head in the race. Yes, economics feed into (actually DRIVE) most drug development big-time.
No actual tests or trials in humans yet means the 10, 15, 20-ish(?) year and multiBillion dollar clock (to "the clinic") is just starting. Our grandkids may get a real benefit. Warming potential---out there. Time is rarely on our side with cancer. But hope matters.
We old dogs fighting the very heterogeneous, clever and dynamically mutating PCa scourge RIGHT NOW, need to go to war with the army we've got, day by day. (Cliché sequencing is such fun...)
Bless these researchers trying to move the game forward.
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